Immune Checkpoint Inhibitors Linked to Range of Adverse Heart Effects

Patients with cancer treated with immune checkpoint inhibitors (ICIs) had a significantly higher incidence of major adverse cardiovascular events (MACE), exceeding prior estimates, a retrospective cohort analysis showed.

During a median follow-up of 13 months, 10.3% of patients treated with ICIs experienced MACE, and the median time to MACE was 5 months. A matched-cohort analysis of cancer patients treated with non-ICI therapies showed a 39% lower risk of MACE. The magnitude of risk reduction increased to 76% in a comparison of the ICI group versus a cohort with no history of cancer.

MACE had a significant association with baseline cardiovascular risk factors, particularly heart failure (HF) and valvular heart disease (VHD), but the magnitude of difference from the non-ICI and noncancer cohorts suggested a potentially harmful cardiovascular effect beyond underlying risk, reported Dorien Laenens, MD, of University Hospitals Leuven in Belgium, and co-authors in the Journal of Clinical Oncology (JCO).

“Treatment with ICIs is associated with a higher incidence of adverse cardiovascular events in real-world practice than that traditionally reported in trial settings,” the authors concluded. “A cardiovascular history, especially a history of HF or VHD, makes patients with cancer vulnerable to these adverse events. A routine thorough cardiovascular history, ECG, and echocardiography might identify patients who need a regular cardiovascular follow-up during and after ICI treatment.”

Treatment with ICIs has a well-known association with myocarditis, but information about other cardiovascular effects has been lacking, with the exception of anecdotal and case reports. The Belgian study provides new and useful information in that respect, noted cardiologist Nicolas Palaskas, MD, of the University of Texas MD Anderson Cancer Center in Houston.

However, the study is not the first of its kind. Another recent matched-cohort analysis compared atherosclerotic events in 2,842 cancer patients treated with ICIs and 2,842 patients who received non-ICI therapies. Treatment with an ICI was associated with a fourfold increased risk in the composite endpoint. Individual components of the composite endpoint increased similarly. Moreover, a comparison of the composite event rate before and after initiation of an ICI showed more than a fourfold increase in events after initiation.

“So, overall the information in the JCO article is not the first time this has been reported, but is only the second large study with a control arm comparing cardiovascular events [that] are not myocarditis,” Palaskas told MedPage Today via email. “It adds to the literature and the hypothesis that the increased inflammation from ICI use leads to increased cardiovascular events.”

“The exact mechanisms are not known; however, atherosclerosis is an inflammatory disease, and the hypothesis is that the increased inflammation from ICI leads to increased atherosclerosis,” he added.

Laenens and colleagues sought to quantify the incidence of MACE in patients with cancer treated with ICIs. Investigators defined MACE as the composite of acute coronary syndrome (ACS), HF, stroke, and transient ischemic attack. Previous studies, using different definitions for events, showed cumulative event rates of 4.2% to 9.7%.

The researchers identified 672 patients treated with ICIs from June 2010 to January 2020 following cancer diagnosis during January 1975 to December 2019. The positive control group comprised 790 patients with cancer treated with non-ICI therapies (primarily after January 2000). The noncancer control group consisted of 3,343 patients enrolled in an observational study of environmental and genetic effects on health.

The matched analysis included 421 patients treated with ICIs, 396 patients with cancer who received non-ICI treatment, and 399 from the noncancer control group.

Among all patients treated with ICIs, 54.9% died, with a 1.9% incidence of cardiovascular mortality. Overall, 69 of the 672 patients had a qualifying MACE. The matched-cohort comparison showed 44 of 421 had a MACE, which translated into a rate of 8.51 per 100 patient-years, as compared with 5.23 for the non-ICI patients with cancer and 1.91 for the noncancer control group. Similar differences existed for comparisons of ACS and HF.

A multivariable analysis showed that a history of HF (HR 2.27, 95% CI 1.03-5.04, P=0.043) or VHD (HR 3.01, 95% CI 1.05-8.66, P=0.041) were independently associated with the risk of MACE.

“This analysis showed a significantly higher incidence of MACE in the matched ICI group, representative for the full ICI cohort,” the authors wrote. “HRs adjusted for the competing risk of death confirmed a significantly higher probability of developing MACE in the ICI group.”

“Secondary outcome analysis revealed a modest, although statistically nonsignificant overweight of HF events, likely responsible for these findings,” they added. “This suggests a harmful effect of ICI treatment besides the underlying risk profile.”

Correction: An earlier version stated that Palaskas is affiliated with the Parker Institute.

Please enable JavaScript to view the comments powered by Disqus.